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A Novel Model of Canine
Hemangiosarcoma:
New Opportunity to Confront a Killer
N Akhtar1, ML Padilla1, EB Dickerson1, H Steinberg2,
M Breen3, R Auerbach4,5,
SC Helfand1,5, 1Departments of Medical Sciences
and 2Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI; 3Department
of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC; 4Laboratory
of Developmental Biology, University of Wisconsin-Madison; 5University of Wisonsin Comprehensive Cancer Center,
Madison, WI
Increasingly,
it has become more important to develop models of naturally occurring canine cancer than can be systematically examined in
the laboratory. These efforts help us to better understand fundamental cellular
derangements, identify potential therapeutic targets, and test novel therapies. Hemangiosarcoma
(HSA) arises from transformed vascular endothelial (blood vessel) cells. This
tumor represents greater than, or equal to, 7% of all canine malignancies, and it is more commonly seen in male dogs between
8 and 10 years old. German shepherd dogs are at greatest risk for HSA, but Golden
Retrievers, Great Danes, Boxers, English Setters, and Pointers are also over represented breeds. The spleen, right atrium, and subcutis are the most common sites for primary HSA in dogs. Local infiltration and systemic metastases are the common growth patterns.
Metastatic sites are widespread with the lung and liver being the most frequently affected organs. Splenic rupture results in tumor implants throughout the abdomen.
Morbidity and mortality is often due to acute internal hemorrhage secondary to tumor rupture. Despite surgery and intensive chemotherapy, the median survival time for dogs diagnosed with HSA is little
more than six months.
We
established a canine hemangiosarcoma cell line derived from malignant endothelial cells comprising a spontaneous tumor in
a dog to provide a renewable source of endothelial cells for studies of angiogenesis, the formation of new blood vessels,
in malignancy. Pieces of the hemangiosarcoma biopsy were engrafted subcutaneously
in a bg/nu/XID (immunodeficient) mouse allowing the tumor cells to expand in vivo. A
cell line, SB-HSA, was derived from the xenograft. SB-HSA cells expressed vascular
endothelial growth factor (VEGF) receptors-1 and –2, CD31, CD146, avB3 integrin, and produced
several growth factors and cytokines, including VEGF, basic fibroblast growth factor, and interleukin (IL) –8 that are
stimulatory to endothelial cell growth. These results indicated that the cells
recapitulated features of mitotically activated endothelia. In vivo, SB-HSA cells
stimulated robust angiogenic responses in mice and formed tumor masses composed of aberrant vascular channels in immunocompromised
mice that mimicked canine HSA, providing novel opportunities for investigating the effectiveness of antiangiogenic agents. Using this model, we determined that IL-12, a cytokine with both immunostimulatory
and antiangiogenic effects, suppressed angiogenesis induced by and tumor growth of SB-HSA cells. The endothelial cell model we have described offers unique opportunities to pursue further investigations
with IL-12, as well as other antiangiogenic approaches in cancer therapy, with special emphasis on canine HSA.
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